Certain sulfamylbenzoic acids, esters thereof, and pharmaceutically acceptable salts thereof

ABSTRACT

The invention relates to a series of new compounds, their salts and esters and to methods for the preparation of the compounds having the general formula:   IN WHICH THE NH-R1 group can be in the 2- or 3-position, R1 represents an aliphatic radical with from three to eight carbon atoms in the chain, or a mononuclear aromatically or a mononuclear heterocyclically substituted methyl or ethyl group, and R2 represents an unsubstituted or substituted phenyl group. The compounds of the invention possess pronounced diuretic and saluretic activities.

- [22] Filed:

United States Patent n 1 Feit et al.

[ 1 Sept. 11, 1973 CERTAIN SULFAMYLBENZOIC ACIDS,

ESTERS THEREOF, AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF [75]Inventors: Peter Werner Feit, Gentofte; Ole

Bent lvaermose Nielsen, Vanlose, both of Denmark [73 Assignee: LovensKemiske Fabrik Produktionsaktieselskab, Ballerup, Denmark June 16, 1971[21] Appl. No.: 153,879

[30] Foreign Application Priority Data June 18,1970 Great Britain,29,742/70 [56] References Cited UNITED STATES PATENTS 3,058,882 10/1962Sturm et al. ..260/397.7

3,250,764 5/1966 Schmidt et al 260/465 D 3,565,920 2/1971 Werner260/347.2 3,678,039 7/1972 Werner et al 260/397.7

OTHER PUBLICATIONS Roberts et al., Basic Principles of OrganicChemistry, Benjamin Publishers, Page 806, 1965.

Primary Examiner-Alan L. Rotman Attorney-Jackson, Jackson and Chovanes[5 7 ABSTRACT The invention relates to a series of new compounds, theirsalts and esters and to methods for the preparation of the compoundshaving the general formula:

in which the NH-R, group can be in the 2 or 3- position, R represents analiphatic radical with from three to eight carbon atoms in the chain, ora mononuclear aromatically or a mononuclear heterocyclically substitutedmethyl or ethyl group, and R represents an unsubstituted or substitutedphenyl group.

The compounds of the invention possess pronounced diuretic and salureticactivities.

24 Claims, No Drawings CERTAIN SULFAMYLBENZOIC ACIDS, ESTERS THEREOF,AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF This invention relates toa series of new compounds, their salts and esters and to methods for thepreparation of the compounds having the general formula:

4 a NH-R; ROH 2 CODE in which the Nl-l'R group can be in the 2- or 3-position, R represents an aliphatic radical with from three to eightcarbon atoms in the chain, or a mononuclear aromatically or amononuclear heterocyclically substituted methyl or ethyl group, and R,represents an unsubstituted or substituted phenyl group.

In particular, R, may represent a straight or branched alkyl radical,having from three to eight carbon atoms, e.g. a propyl, isopropyl,butyl, isobutyl, or tert. butyl radical, or one of the differentisomeric pentyl, hexyl, or heptyl radicals, an alkenyl or alkynylradical, e.g. an allyl, or propargyl radical. In the mononucleararomatically or mononuclear heterocyclically substituted aliphaticradicals the aromatic part of the radical can be an unsubstituted orsubstituted phenyl radical and the heterocyclic part of the radical canbe a monocyclic radical with one or more oxygen, sulphur and nitrogenatoms as ring members, e.g. 2-, 3- or 4-pyridyl, 2- or 3- furyl or-thienyl, thiazolyl, imidazolyl. Illustrative examples of sucharomatically or heterocyclically substitued aliphatic radicals arebenzyl, lor 2- phenylethyl, furyl-methyl and thienyl-methyl, or thecorresponding ethyl radicals.

The substituents R and R, of formula (I) can be substituted in differentpositions with different groups, such as one or more halogen atoms, e.g.chlorine or bromine atoms, lower alkyl, halo-lower alkyl, e.g.trifluoromethyl, chloromethyl, 2-chloroethyl, dichloromethyl,trichloromethyl or bromomethyl; carboxy, carb(lower)alkoxy or carbamylradicals; di-lower alkylamino radicals, hydroxy groups, which may beetherified, e.g. lower alkoxy such as methoxy, ethoxy, n-propoxy,isopropoxy, n -butoxy or isobutoxy'; or esterified with lower aliphaticcarboxylic acids, such as lower alkanoic acids, e.g. acetic, propionicor pivalic acid, lower alkenoic acids, e.g. acrylic or methacrylic acid,lower aliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic,glutaric, adipic, maleic or fumaric acid or their halfesters with loweralkanols, e.g. methanol or ethanol; or etherified mercapto groups suchas methylthio, ethylthio, isopropylthio, butylthio or isobutylthio.

Whenever the expression "lower alkyl" is used in the foregoing and inthe following it stands for a straight or branched alkyl radical withfrom one to six carbon atoms in the chain.

Among the preferred compounds of the invention mention may be made ofcompounds in which R, in formula (I) stands for alkyl with from three tofive carbon atoms in the carbon chain, or for benzyl, furylmethyl orthienylmethyl, these examples, however, not being considered limitingfor the invention.

The salts of the compounds of the invention are pharmaceuticallyacceptable salts, and include, for example, alkali metal salts, alkalineearth metal salts, the ammonium salt, or amine salts fonned, forinstance, from mono-, dior trialkanolamines or cyclic amines. The estersof the compounds are preferably derived from lower aliphatic alcohols,cyanomethanol and benzylalcohols.

In animal experiments the compounds of the invention possess anoutstanding diuretic and saluretic activity. Thus for example, potenciesapproximately of times that of the well-known furosemide with regard tourinary excretion of water and sodium ions have been demonstrated.Furthermore was observed a very favourable ratio between the excretionof sodium ions and potassium ions which in connection with a lowtoxicity make the present compounds particularly valuable.

The present compounds are effective after oral, enteral or parenteraladministration, and are in human or veterinary practice preferablyprescribed in the form of tablets, pills, dragees, or capsulescontaining the free acid or salts thereof with atoxic bases, or theesters thereof, mixed with carriers and/or auxiliary agents.

Salts, which are soluble in water, may with advantage be administered byinjection. The compounds of the invention are useful in the treatment ofoedematous conditions e.g. cardiac, hepatic, renal, lung and brainoedema, or oedematous conditions during pregnancy, and of pathologicalconditions which produce an abnormal retention of the electrolytes ofthe body, and in the treatment of hypertension.

In pharmaceutical compositions containing the compounds of theinvention, organic or inorganic, solid or liquid carriers suitable fororal, enteral or parenteral administration can be used to make up thecomposition. Gelatine, lactose, starch, magnesium stearate, talc,vegetable and animal fats and oils, gum, polyalkylene glycol, or otherknown carriers for medicaments are all suitable as carriers.

The compositions may further contain other therapeutic compounds appliedin the treatment of, for example oedemas and hypertension, besides thewellknown auxiliary agents. Such other compounds may be, for instance,Veratrumor Rauwolfia alkaloids, e.g. reserpine, rescinnamine orprotoveratrine or synthetic hypotensive compounds, e.g. hydralazine, orother diuretics and saluretics, such as the well-knownbenzothiadiazines, e.g. hydroflumethiazide, bendroflumethiazide, and thelike..Potassium-sparing diuretics, e.g. triamterene, may also be used inthe preparation of the compositions. For some purposes it may bedesirable to add small amounts of carboanhydrase inhibitors oraldosterone antagonists, e.g. spironolactone.

In human therapy it has been found that the compounds and their saltsshall conveniently be administered in dosage units containing not lessthan 0.1 mg, and up to 25 mg., preferably in doses of from 0.25 to 2.5mg., once, twice or thrice a day, calculated as the free acid of formulaI, to achieve the desired activity without simultaneous secondaryeffects, the prescription, however, always being with due regard to thecondition of the patient and under the direction of a medicalpractitioner.

By the term dosage unit" is meant a unitary, i.e. a single dose which iscapable of being administered to a patient, and which may be readilyhandled and packed, remaining as a physically stable unit dose com-'case of oedemas in the lung. In the continuous therapy of patientssuffering from e.g. hypertension, the tablets or capsules'may be theappropriate form of pharmaceutical preparation owing to the prolongedeffect obtained when the drug is given orally, in particular in the formof sustained -release tablets.

in the treatment of heart failure and hypertension such tablets mayadvantageously contain other active components, as specifiedhereinbefore.

It is another object of the invention to provide a method of producingthe compounds of the invention. In one embodiment compounds of formula(I) are provided in a reaction which comprises the alkylation of acompound of the general formula:

3 NH I RQCH 2 4 CODE in which R has the meaning hereinbefore defined.

Appropriately the alkylation can be performed either on the free acid offormula (ll) or on one of its esters by reaction with a compound of theformula R X, R, being as defined before and X being a halogen atom,preferably the compound or bromine, a hydroxyl group, or a sulphonyloxygroup, an alkylor arylsulphonyloxy group, the carboxylic acid groupsubsequently being liberated, if desired.

The alkylation processes are well-known to the man skilled in the artand are e.g. described in the complete specification to our SouthAfrican patent No. 69/8615.

The starting substances of formula (ll) are hitherto unknown compoundswhich can be prepared by several methods of which a preferred methodcomprises the step of exposing a compound of the general formula:

S C OOH to the well-known Wolff-Kishner reaction condition, whereafterthe corresponding compound of formula (ll) is obtained from the reactionmixture after acidification.

Also the compounds of formula (III) are unknown compounds whichdepending on the position of the amino group attached to the benzenenucleus are provided .by different methods. Thus, when the amino groupisplaced in the 4-position, 4-carbethoxy-2,6- dinitrobenzoic acid isused as starting material in a preferred route for the preparation ofthe compound of formula (III). This starting material is transformedinto the corresponding acid chloride by treatment with a chlorinatingagent, such as thionyl chloride or phosphorus chlorides. By treatment ofthis acid chloride with benzene and aluminum chloride under wellknownconditions and isolation. of the reaction product, ethyl4-benzoyl-3,S-dinitrobenzoate is obtained. By replacing the benzene inthe reaction above with substituted benzene the corresponding ethyl4-(substituted benzoyl)-3,5-dinitrobenzoate is obtained.

After saponification to the corresponding free acid, this is partiallyreduced by means of a reducing agent, such as an alkali dithionitewhereby only one of the nitro groups is converted into an amino group.The obtained 5-amino-4-benzoyl-3-nitrobenzoic acid is subjected to aMeerwein-reaction, whereby 4-benzoyl-5- chlorosulphonyl-3-nitrobenzoicacid is obtained, which after treatment with ammonia yields thecorresponding 5-su'lphonamide of the general formula:

M NO:

' H,N0,s 5 1 00011 in which R has the meaning hereinbefore defined.After a further reduction of the nitro group in the .3- position, forinstance with an excess of sodium -dithionite, and at slightly elevatedtemperature, a ring closure takes place preferably under acidicconditions and the compound of formula (Ill) is obtained, having theamino group in the 4-position.

Optionally, the compound of formula (IV) can directly be converted intothe desired starting substance of formula (ll), the nitro group beingreduced while performing the Wolff-Kishner reaction mentionedhereinbefore.

The compounds of formula (Ill) in which the amino group is placed in the5-position are appropriately obtained from4-acetamino-2-chloro-5-nitrobenzoic acid as starting material. Thiscompound is converted into the corresponding benzoyl chloride bytreatment with a chlorinating agent such as thionyl chloride which bytreatment with benzene and aluminum chloride is converted into thecorresponding 4-acetamino-2-chloro-5- nitrobenzophenone. By an acidichydrolysis 4-amino-2- chloro-5-nitrobenzophenone is obtained.

By diazotation and treatment with cuprous cyanide the amino group of theabove mentioned compound is converted into a nitril, which again by anacid hydrolysis is transferred into the corresponding acid. This 4-benzoyl-S-chloro-2-nitrobenzoic acid is by reacting withbenzylmercaptane converted to the corresponding S-benzylthio compoundwhich by an oxydative chlorination using chlorine in e.g. acetic acidyields the 5- chlorosulphonyl derivative. By treatment of this reactionproduct with ammonia below or at room temperature an intermediate isformed which without isolation and under simultaneous ring closure isconverted into 6-carboxy-5-nitro-3-phenyl-l ,2-benzisothiazole-l ,1dioxide. The nitro group of this compound is reduced to an amino groupby a mild reduction for instance with ferrosulphate in ammoniumhydroxide, whereby the compound of formula III is obtained. Thesubstituted 3- phenyl-derivatives are prepared in analogous reactions.

in another embodiment of the invention the com pounds of formula (1) areobtained by exposing a compound of the general formula:

-COOH in which R and R have the meaning hereinbefore defined toWolff-Kishner reaction conditions. The compounds of formula (V) areknown compounds the preparation of which is described in our BritishPatent Application No. 3l7l8/70.

The compounds of formula (I) thus produced in the various embodimentsmay be obtained in the form of the free acid, its salts or one of itsesters, of which the esters, if desired, are saponified and vice verse.

For use in the therapy various pharmaceutically acceptable esters of thecompounds of formula (I) are interesting, as for instance esters withlower aliphatic alcohols, including diethylaminoethanol, and with otherwell-known and commonly used non-toxic alcohols.

The invention will now be illustrated by the following non-limitingexamples from which the details of the embodiments will be apparent.

EXAMPLE 1 2-Amino-4-benzyl-S-sulfamylbenzoic acid A.4-Acetamino-2-chloro-S-nitrobenzophenone A mixture of4-acetamino-2-chloro-5-nitrobenzoic acid (26 g.) and thionyl chloride(100 ml.) is refluxed for about 1 hour, and the resulting solutionevaporated in vacuo. The crude 4-acetamino-2-chloro-5- nitrobenzoylchloride obtained is dissolved in dry benzene (300 ml.) and anhydrousaluminum chloride (26 g.) is added in portions, while stirringvigorously at 40 -50 C.. The mixture is stirred at room temperature forabout hours and then refluxed for about 1 hour. The resulting solutionis poured into a mixture of ice (about 1 kg.) and concentratedhydrochloric acid (50 ml.). The resulting precipitate is filtered offand dissolved in chloroform (about 500 ml.), which is washed with water,dried (MgSO,) and evaporated in vacuo. The residue is crystallized fromethanol and collected by filtration. After drying and recrystallizationfrom a mixture of ethanol and methylcellosolve, 4-acetamino-2-chloro-S-nitrobenzophenone is obtained with a melting point of l82-l83C. From the benzene layer of the mother liquors a further crop with thesame melting point can be obtained. B.4-Amino-2-chloro-5-nitrobenzophenone A mixture of4-acetamino-2-chloro-5- nitrobenzophenone (22 g.), ethanol (300 ml.) andconcentrated hydrochloric acid (200 ml.) is refluxed for about 2 hours.On cooling, the separated oil crystallizes. The material is collected byfiltration and washed with cold aqueous ethanol. After drying andrecrystallization from aqueous ethanol, 4-am'ino-2-chloro-5-nitrobenzophenone is obtained with a melting point of l49-l50 C. C.2-Chloro-4-cyano-5-nitrobenzophenone A solution of 4-amino- -chloro-5-nitrobenzophenone (13.8 g.) in acetic acid (100 ml.)

is slowly added to nitrosylsulfuric acid prepared from sodium nitrite(4.0 g.) and concentrated sulfuric acid (28 ml.), while stirring at roomtemperature. The resulting dia'zonium-solution is stirred at roomtemperature for a further 2 hours, and is then added dropwise to asolution of potassium cyanide (50 g.), cuprous cyanide (25 g.) andanhydrous sodium carbonate (250 g.) in water (700 ml.) in the presenceof an upper benzene layer and while stirring vigorously at 65-70 C.After the addition is completed, the mixture is stirred until it hasreached room temperature. The benzene layer is then separated and theaqueous layer extracted twice with benzene. The combined benzenefractions are washed with water, dried (MgSO and evaporated in vacuo.The residue is crystallized with ethanol, filtered off and washed withethanol and with petroleum ether. After drying and recrystallizationfrom a mixture of ethanol and methylcellosolve, 2-chloro-4-cyano-5-nitrobenzophenone is obtained with a melting point of 133 l35 C.. D.4-Benzoyl-5-chloro-2-nitrobenzoic acid To the crude4-cyano-2-chloro-S-nitrobenzophenone (about g.) prepared from4-amino-2-chloro-5- nitrobenzophenone (94 g.) as described in Example 1step C, concentrated sulfuric acid (650 ml.) and water (450 ml.) isadded, and the mixture stirred at ll85 C. for 2 hours. After cooling,water (about 1 l.) is added and the mixture is left in a refrigeratorfor about 20 hours. The separated material is collected by filtrationand washed with water. It is then extracted with boiling sodiumhydrogencarbonate solution (saturated, about 500 ml.) which is filteredhot in the presence of decolourizing carbon. The filtrate is cooled andthen carefully acidified with concentrated hydrochloric acid ml.). Theresulting precipitate is filtered off and washed with water. Afterdrying and recrystallization from aqueous ethanol, 4-benzoyl-5-chloro-2-nitrobenzoic acid is obtained with a meltingpoint of 2092l 1 C.. E.4-Benzoyl-5-benzylthio-2-nitrobenzoic acid A mixture of4-benzoyl-5-chloro-2-nitrobenzoic acid (35 g.), sodium hydrogencarbonate(30 g.), benzylmercaptane (30 ml.) and water (300 ml.) is heated on asteam bath for about 6 hours. The mixture is then cooled and carefullyacidified with concentrated hydrochloric acid (50 ml.). The separatedoil is extracted with diethyl ether (about 500 ml.) which is washed withwater, dried (MgSOJ and evaporated in vacuo. The residue is crystallizedby trituration with petroleum ether, collected by filtration and washedwith petroleum ether. After drying and recrystallization from aqueousethanol, 4-benzoyl-5-benzylthio-2- nitrobenzoic acid is obtained with amelting point of l56l57 C.. F.6-Carboxy-5-nitro-3-phenyl-1,2-benzisothiazolel,l-dioxide A mixture of4-benzoyl-5-benzylthio-2-nitrobenzoic acid (43 g.) and acetic acid (250ml.) containing water (8 ml.) is cooled to about 5 C.. An excess ofchlorine is then bubbled through the stirred mixture, keeping thetemperature below 15 C.. After about 3.5 hours, excess chlorine is blownout of the reaction mixture with a stream of nitrogen, followed bydilution with cold water (250 ml.). The precipitated 4-benzoyl-5-chlorosulfonyl-2-nitrobenzoic acid is collected by filtration and washedwith cold water. The damp filter cake is added in portions toconcentrated ammonium hydroxide (400 ml.), while stirring at l0-l2 C..After additional stirring at room temperature for about 20 hours, thereaction mixture is carefully acidified with concentrated hydrochloricacid (about 75 ml.). The resulting precipitate is collected byfiltration and washed with water. After drying, the material issuspended in ethanol (100 ml.) and stirred at room temperature for 1hour. After filtration, drying and recrystallization from ethanol,G-carboxy-S-nitro- 3-phenyl-1,2-benzisothiazole-1,l-dioxide is obtainedwith a melting point of 277-280 C. (dec.). G.S-Amino-6-carboxy-S-phenyl-1,2-benzisothiazole- 1,1-dioxide A solutionof 6-carboxy-5-nitro-3-phenyl-l,2- benzisothiazole-l ,l-dioxide (3.3 g.)in concentrated ammonium hydroxide (70 ml.) is added in portions to awarm solution of ferrosulfate heptahydrate (20 g.) in water (60 ml.).The reaction mixture is heated on a steam bath for a further 20 minutesand is then filtered hot. The filtrate is concentrated in vacuo to about50 ml. and is then carefully acidified to pH 2.0 with hydrochloric acid.The resulting precipitate is collected by filtration and washed withwater. After drying and recrystallization from a mixture of ethanol andmethylcellosolve,-amino-6-carboxy-3-phenyl-l,2-benzisothiazole-l,l-dioxide is obtainedwith a melting point higher than 285 C.. H.2-Amino-4-benzyl-5-sulfamylbenzoic acid A mixture of5-amino-6-carboxy-3-phenyl-l,2- benzisothiazole-l,l-dioxide (3.0 g.), 80percent aqueous hydrazine hydrate (6.0 ml.), potassium hydroxide (2.0g.), water (4.0 ml.) and diethylene glycol (25 ml.) is stirred at130-140 C. for 3 hours. The temperature is then slowly raised to 215 C.allowing volatile material to distil off. The stirring at 215 C. iscontinued for a further 3 hours. After cooling and dilution with waterml.), the reaction mixture is acidified with concentrated hydrochloricacid (5 ml.). The resulting precipitate is collected by filtration andwashed with water. After drying, and recrystallization from ethanol 2-amino-4-benzyl-5-sulfamylbenzoic acid is obtained with a melting pointof 253-255 C. (dec.).

, EXAMPLE 2 3-Amino-4-benzyl-S-sulfamylbenzoic acid.

A. Ethyl 4-benzoyl-3,S-dinitrobenzoate A mixture of4*carbethoxy-2,6-dinitrobenzoic acid (85 g.), thionylchloride (85 'ml.)and pyridine (0.25 ml.) is refluxed for about 3 hours. The resultingsolution is evaporated in vacuo and the remaining 4-carbethoxy-2,6-dinitrobenzoyl chloride is dissolved in dry benzene (130ml.). Anhydrous aluminum chloride (50 g.) is then added in portions tothe refluxing solution while stirring vigorously. After the addition iscompleted, the mixture is stirred and refluxed for a further 2 hours.After cooling to about 50 C., methylene chloride (250 ml.) is addedfollowed by a mixture of ice (250 g.) and concentrated hydrochloric acid(150 ml.). After additional stirring for about 1 hour, the organic layeris separated, washed with water and evaporated in vacuo. The residue istriturated with hot ethanol (200 ml.) and, after cooling, the resultingprecipitate is collected by filtration, and washed with cold ethanolfollowed by petroleum ether. After drying and recrystallization frommethylcellosolve, ethyl 4-benzoyl-3,5-

To a stirred suspension of ethyl 4-benzoyl-3,5- dinitrobenzoate (160 g.)in ethanol (800 ml.), 2 N sodium hydroxide (260 ml.) is added dropwisewithin 15 minutes. After additional stirring for 10 minutes, theresulting solution is clarified by filtration and is then acidified bythe addition of 4 N hydrochloric acid (150 ml.). After cooling, theresulting precipitate is collected by filtration and washed with water.After drying and recrystallization from aqueous ethanol, 4-benzoyl-3,5-dinitrobenzoic acid is obtained with a melting point of 248251 C(dec.).

C. 5-Amino-4-benzoyl-3-nitrobenzoic acid A mixture of4-benzoyl-3,S-dinitrobenzoic acid (1 10 g.) and pyridine (220 ml.) isheated on a steam bath for about 15 minutes to afford the formation ofthe pyridinium-salt. Water (440 ml.) is then added and the mixture iscooled to 2022 C.. To the stirred mixture, sodium dithionite (124 g.) isthen added in portions during 7-8 minutes keeping the temperature at20-22 C.. After the addition is completed the stirring is continued fora further 6-7 minutes allowing the temperature to drop to l2l5 C.. Theresulting red solution is carefully acidified with concentratedhydrochloric acid (380 ml.) keeping the temperature below 22 C.. Thereaction mixture is left at room temperature for about 20 hours. Theprecipitated material is then collected by filtration and washed withwater. After recrystallization from acetonitrile, 5-amino-4-benzoyl-3-nitrobenzoic acid is obtained with a melting point of 203-204 C. (dec.).D. 4-Benzoyl-3-nitro-5-sulfamylbenzoic acid A mixture of5-amino-4-benzoyl-3-nitrobenzoic acid (28.6 g.) and concentratedhydrochloric acid ml.) is heated on a steam bath for about 10 minutesand then cooled. The amine is diazotized by dropwise addition of asolution of sodium nitrite(7.6 g.) in water (40 ml.) while stirring at0-5 C.. The resulting diazoniummixture is poured into a solution ofcupric chloride dihydrate (4.0 g.) in water (15.0 ml.) and acetic acidml.) saturated with 80,, while stirring at room temperature. Thestirring is continued for a further 1 hour and the mixture is thendiluted with cold water (300 ml. The precipitated 4-benzoyl-5chlorosulfonyl-3-nitro-benzoic acid is collected by filtration andwashed with water. The damp filter-cake is then added in portions toconcentrated ammonium hydroxide (300 ml.) while stirring at l0-l 2 C..After additional stirring at room temperature for j about 20 hours, thesolution is carefully acidified to pH 2.0 with concentrated hydrochloricacid. The resulting precipitate is collected by filtration and washedwith water. After drying and recrystallization from aqueous ethanol,4-benzoyl-3-nitro-5-su1famylbenzoic acid is obtained with a metlingpoint of 234235 C..

E. 4-Amino-6-carboxy-3-phenyl-l,2-benzisothiazole- 1,1-dioxide To astirred solution of 4-benzoyl-3-nitro-5- sulfamylbenzoic acid (7.0 g.)in a mixture of pyridine 65 dlnitrobenzoate is obtained with a meltingpoint of 172173 C.. B. 4-Benzoyl-3,S-dinitrobenzoic acid (15 ml.) andwater (50 ml.), sodium dithionite (14 g.) is added in portions.Themixture is heated on a steam bath for about 1 hour and is thenevaporated in vacuo. The remaining material is dissolved in hot water(about 50 ml.) and the solution is acidified with concentratedhydrochloric acid (15 ml.). The mixture is heated on a steam bath for 15minutes and left at room temperature for about 20 hours. The resultingprecipitate is collected by filtration and washed with'water. Afterdrying and recrystallization from a mixture of acetonitrile andmethylcellosolve, 4-amino-6-carboxy-3-phenyl-l ,2-benzisothiazole-l,l-dioxide is obtained with a melting point of 287-288C. (dec.). F. 3-Amino-4-benzyl-5-sulfamylbenzoic acid By replacing inExample 1 step H -amino-6- carboxy-3-phenyl-l ,2-benzisothiazole-l l-dioxide by 4-amino-6-carboxy-3-phenyl-l ,2-benzisothiazole-l l dioxide,3-amino-4-benzyl-5-sulfamyl-benzoic acid is obtained with a meltingpoint of 285-286 C.(dec.).

EXAMPLE3 3-Amino-4-( 4'-methylbenzyl)-5-sulfamylbenzoic acid.

A. Ethyl 3,5 -dinitro-4-(4'-methylbenzoyl)-benzoate To a solution of2,6-dinitro-4-carbethoxybenzoyl chloride (prepared from2,6-dinitro-4-carbethoxybenzoic acid (110 g.) according to the proceduredescribed in Example 2 step A) in a mixture of dry toluene (550 ml.) andcarbondisulfide (550 ml.), anhydrous aluminum chloride (160 g.) is addedin portions while stirring vigorously at room temperature. After theaddition is completed, the stirring is continued for a further 2 hoursfollowed by refluxing for 2 hours. The mixture is then poured into amixture of ice (about 2 kg.) and concentrated hydrochloric acid (500ml.). After dilution with methylene chloride (500 ml.), the organiclayer is separated, washed with water and evaporated in vacuo. Theresidue is triturated with hot ethanol (300 ml.) and, after cooling, theresulting precipitate is collected by filtration and washed with coldethanol followed by petroleum ether. After drying and recrystallizationfrom a mixture of ethanol and methylcellosolve, ethyl3,5-dinitro-4-(4'-methylbenzoyl)- benzoate is obtained with a meltingpoint of l77.5l7-

C.. B. 3,5-Dinitro-4-(4-methylbenzoyl)-benzoic acid By replacing inExample 2 step B ethyl 4-benzoyl-3,S-dinitrobenzoate by ethyl3,5-dinitro4- (4'-methylbenzoyl)-benzoate, 3,5-dinitro-4-(4'-methylbenzoyl)-benzoic acid is obtained with a melting point of 266-268C.. C. 5-Amino-4-(4'-methylbenzoyl)-3-nitrobenzoic acid By replacing inExample 2 step C 4-benzoyl-3,5- dinitrobenzoic acid by3,5-dinitro-4-(4-methylbenzoyl)-benzoic acid,5-amino-4-(4-methylbenzoyl)-3- nitrobenzoic acid is obtained with amelting point of 223;5-225 C.. D.4-(4'-Methylbenzoyl)-3-nitro-5-sulfamylbenzoic acid By replacing inExample 2 step D 5-amino-4 benzoyl- El-nitrobenzoic acid by5-amino-4-(4'-methylbe'nzoyl)- 3-nitrobenzoic acid, 4-(4'-methylbenzoyl)3-nitro-5- sulfamylbenzoic acid is obtained with a melting point of23l-232 C.. E. 4-Amino-6-carboxy-3-(4'-methylphenyl)-l ,2-benzisothiazole-1,1-dioxide By replacing in Example 13-phenyl-l,2benzisothiazole-l,l-dioxide by 4-(4'-methylbenzoyl)-3-nitro-5-sulfamylbenzoic acid, 4-amino-6-carboxy-3-(4-methylphenyl)-1,2-benzisothiazole-l ,l-dioxide isobtained with a melting point of 32l.5-324.5 C. (dec.). F.3-Amino-4-(4'-methylbenzyl)-5-sulfamylbenzoic acid By replacing inExample 1 step H 5-amino-6- carboxy-3-phenyll ,2-benzisothiazole-l l-dioxide by 4-amino-6-carboxy-3-(4'-methylphenyl)-l ,2-benzisostep G6-carboxy-5-nitrothiazole-l,l-dioxide, 3-amino-4-(4'-methylbenzyl)-5-sulfamylbenzoic acid is obtained with a melting point of 296-298 C..

EXAMPLE 4 By replacing in Example 2 step B the ethyl4-benzoyl-3,S-dinitrobenzoate by ethyl 4-(2',4'-dimethylbenzoyl)-3,S-dinitrobenzoate, 4-(2,4-

dimethylbenzoyl)-3,5-dinitrobenzoic acid is obtained with a meltingpoint of 243-245 C.. C. ,5-Amino4-(2',4'-dimethylbenzoyl)-3-nitrobenzoic acid By replacing in Example 2step C 4-benzoyl-3,5- dinitrobenzoic acid by4-(2',4-dimethylbenzoyl)-'3,5- dinitrobenzoic acid,5-amino-4-(2',4'-dimethylbenzoyl)-3-nitrobenzoic acid is obtained with amelting point of 245247 C.. D. 4-(2'-4'-Dimethylbenzoyl)-3-nitro-5-sulfamylbenzoic acid By replacing in Example 2 step D 5-amino4-benzoyl-3-nitrobenzoic acid by 5-amino-4-(2',4'-dimethylbenzoyl)-3-nitrobenzoicacid, 4-(2',4'-dimethylbenzoyl)- 3-nitro-5-sulfamylbenzoic acidcrystallizing with 1 mole of acetonitrile is obtained with a meltingpoint of 236-238 C.. E. 3-Amino-4-(2',4'-dimethylbenzyl)-5-sulfamylbenzoic acid By replacing in Example 1 step H 5-amino-6-carboxy-3-phenyl-l ,2-benzisothiazole-l l -dioxide by4-(2',4'-dimethylbenzoyl)-3-nitro-5-sulfamylbenzoic acid,3-amino-4-(2,4'-dimethylbenzyl)-5- sulfamylbenzoic acid is obtained as ahydrate with a melting point of 265-267 C..

EXAMPLE 5 3-Amino-4-(4'-chlorobenzyl)-5-sulfamylbenzoic acid A. Ethyl4-(4'-chlorobenzoyl)-3,S-dinitrobenzoate By replacing in Example 2 stepA benzene by chlorobenzene and performing the reaction at C., ethyl4-(4'-chlorobenzoyl)-3,S-dinitrobenzoate is obtained with a meltingpoint of l62.5-l64 C.. B. 4-(4'-Chlorobenzoyl)-3,S-dinitrobenzoic acidBy replacing in Example 2 step B ethyl 4-benzoyl-3 ,S-dinitrobenzoate byethyl 4-( 4 chlorobenzoyl)-3,S-dinitrobenzoate, 4-(4'- chlorobenzoyl)3,S-dinitrobenzoic acid is obtained with a melting point of 266-267 C..

C. 5-Amino-4-(4-chlorobenzoyl)-3-nitrobenzoic acid.

By replacing in Example 2 step D 5-amino-4-benzoyl-' 3-nitrobenzoic acidby 5-amino-4-(4'-chlorobenzoyl)- S-nitrobenzoic acid,4-(4'-chlorobenzoyl)-3-nitro-5- sulfamylbenzoic acid is obtained with amelting point of 234.5-235.5 C..

E. acid By replacing in Example 1 step H -amino-6- carboxy-S-phenyll,Z-benzisothiazole-l l -dioxide by4-(4'-chlorobenzoyl)-3-nitro-5-sulfamylbenzoic acid,3-amino-4-(4'-chlorobenzyi)-5-sulfamylbenzoic acid is obtained as asemihydrate with a melting point of 304-306 C..

EXAMPLE 6 4-Benzyl-2-benzylamino-5 -sulfamylbenzoic acid A solution of2-amino-4-benzyl-5-sulfamylbenzoic acid (1.0 g.) and benzylbromide (1.0ml.) in methyl- 3-Amino-4-(4'-chlorobenzyl)-5-sulfamylbenzoic cellosolve(5.0 ml.) is heated on a steam bath for 20 7 hours. After cooling, water(5.0 ml.) is added and the resulting precipitate is collected byfiltration and washed with water. After drying and recrystallizationfrom methylcellosolve, I4-benzyl-2-benzylamino-5- sulfamylbenzoic acidis obtained with a melting point of 256-258 C. (dec.).

EXAMPLE 7 4-Benzyl-3-benzylamino-5-sulfamylbenzoic acid A solution of3-amino-4-benzyl-5-sulfamylbenzoic acid (1.5 g.) and benzylbromide (1.5ml.) in methylcellosolve (5.0 ml.) is heated on a steam bath for 18hours. 4 N sodium hydroxide (5.0 ml.) is then added and the heating iscontinued for a further 30 minutes. After cooling, the solution isacidified with 4 N hydrochloric acid (6.0 ml.). The resultingprecipitate is collected by filtration and washed with water. Afterdrying and recrystallization twice from ethanol, 4-benzyl-3-benzylamino-S-sulfamylbenzoic acid is obtained with a melting point of248-249 C. (dec.).

EXAMPLE 8 EXAMPLE 9 3-Benzylamino-4-(4'-methylbenzyl)i5-sulfamylbenzoicacid A mixture of ethyl 3-benzylamino-4-(4'-methylbenzyl)-5-sulfamylbenzoate (0.55 g.) and 2 N sodium hydroxide 5.5ml.) is heated on a steam bath for minutes. The resulting solution iscooled and then acidified with 4 N hydrochloric acid (3.0 ml.). Theresulting precipitate is collected by filtration and washed with water.After drying and recrystallization from ethanol,3-benzylamino-4-(4-methylbenzyl)-5- sulfamylbenzoic acid is obtainedwith a melting point of 236237 C..

EXAMPLES l0-ll By replacing in Example 8 3-amino-4-(4'-methylbenzyl)-5-sulfamylbenzoic acid by 3-amino-4-(2',4'-dimethylbenzyl)-5-sulfamylbenzoic acid and 3-amino-4-(4-chlorobenzyl)-5-sulfamylbenzoic acid, respectively, ethyl3-benzylamino-4-(2,4'- dimethylbenzyl)-5-sulfamylbenzoate and ethyl 3-benzylamino4-(4-chlorobenzyl)-5-sulfamylbenzoate are obtained withmelting points of l50-l5l C. and l68.5l70.5 C. respectively.

EXAMPLES l2l 3 By replacing in Example 9 ethyl 3-benzylamino-4-(4-methylbenzyl)-5-sulfamylbenzoate by the ethyl esters of Examples 10and il, 3-benzylamino-4-(2',4'- dimethylbenzyl)-5-sulfamylbenzoic acidand 3- benzylamino-4-(4'-chlorobenzyl)-5-sulfamylbenzoic acid areobtained with melting points of 245-248 C. and 263.5265 C. respectively.

EXAMPLE l4 Ethyl 3-allylamino-4-benzyl-5-sulfamylbenzoate A solution of3-amino-4-benzyl-5-sulfamylbenzoic acid (2.0 g.) and allylbromide (2.0ml.) in ethanol (30 ml.) is refluxed for 72 hours. After 24 hours and 48hours additional amounts of allylbromide (each time 2.0 ml.) are added.After cooling, the precipitated material is collected by filtration andwashed with cold ethanol followed by petroleum ether. After drying andrecrystallization from aqueous ethanol, ethyl 3-allylamino-4-benzyl-5-sulfamylbenzoate is obtained with a melting pointof l3l.5-l33.5 C..

EXAMPLE l5 3-Allylamino-4-benzyl-S-sulfamylbenzoic acid By replacing inExample 9 ethyl 3-benzylamino-4- (4'-methylbenzyl)-5-sulfamylbenzoate byethyl 3- allylamino-4-benzyl-5-sulfamylbenzoate, 3-allylamino-4-benzyl-5-sulfamylbenzoic acid is obtained with a melting point of2l6-2 l8 C..

EXAMPLE 16 4-Benzyl-3-n-propylamino-5-sulfamylbenzoic acid3-Allylamino-4-benzyl-S-sulfamylbenzoic acid (0.95 g.) dissolved inethanol (15 ml.) is hydrogenated at room temperature in the presence ofPtO (0.1 g.). After about 10 minutesQthe theoretical amount of hydrogenhas been absorbed and the uptake becomes negligible. The catalyst isremoved by filtration and the reaction product is precipitated from thefiltrate by addition of water 10 ml.). The precipitate is collected byfiltration and washed with aqueous ethanol. After drying andrecrystallization from acetonitrile, 4-benzyl-3-n-propylamino-S-sulfamylbenzoic acid is obtained with a melting point of237-238 C..

EXAMPLE l7 4-Benzyl-3-(2',3'-dibromopropylamino)-5'- sulfamylbenzoicacid To a stirred suspension of 3-allylamino-4benzyl-S- sulfamylbenzoicacid (1.74 g.) in acetic acid (25 ml.). a solution of bromine (0.9 g.)in acetic acid (10 ml.) is added dropwise within 30 minutes. Afteradditional stirring for 30 minutes, the resulting solution is slowlydiluted with water (about 75 ml.) to precipitate the reaction product.The precipitate is collected by filtration and washed with water. Afterdrying and recrystallization twice from aqueous ethanol,4-benzyl-3-(2',3- dibromopropylamino)-5-sulfamylbenzoic acid is obtainedwith a melting point of l76l77 C..

EXAMPLE l8 ml.), and the resulting precipitate is collected byfiltration and washed with water. After drying and recrystallizationtwice from aqueous ethanol, 4-benzyl-3-(2'-bromoallylamino)-S-sulfamylbenzoic acid is obtained with a melting pointof 230-232 C..

Example 19 n-Butyl 4-benzyl-3-n-butylamino-5-sulfamylbenzoate A solutionof 3-amino-4-benzyl-5-sulfamylbenzoic acid (1.4 g.) and di-n-butylsulfate (5.5 ml.) in dry toluene (14 ml.) is refluxed for 32 hours.After cooling, the resulting precipitate is collected by filtration andwashed with cold toluene followed by petroleum ether. After drying andrecrystallization twice from aqueous ethanol, n-butyl4-benzyl-3-n-butylamino-5-sulfamylbenzoate is obtained with a meltingpoint of lll-l 13 C..

EXAMPLE 20 4-Benzyl-3-n-butylamirio-5-sulfamylbenzoic acid By replacingin Example 9 ethyl 3-benzylamino-4- (4'-methylbenzyl)-5-sulfamylbenzoateby n-butyl 4- benzyl-3-n-butylamino-5-sulfamylbenzoate, 4-benzyl3-n-butylamino-5-sulfamylbenzoic acid is obtained with a melting pointof 234235 C..

EXAMPLE 21 Sodium salt of sulfamylbenzoic acid To a suspension of3-amino-4'-benzyl-5- sulfamylbenzoic acid (13.5 g.) in n-butanol (400ml.), concentrated sulphuric acid (3.0 ml.) is added. The reactionmixture is then refluxed under such conditions that the water formedduring the reaction is separated. When the NMR-spectrum of a sample ofthe reaction mixture diluted with n-butanol shows that more than 90percent of the n-butyl 3-amino-4-benzyl-5-sulfamylbenzoate intermediateformed is converted into the corresponding 3-n-butylaminobenzoate (whichcauses a frequence shift to higher field of the two doublets of thearomatic protons of the ring carrying the sulfamylgroup) 2 N sodiumhydroxide (100 ml.) is added and the mixture refluxed for a further 30minutes. After this saponification, the reaction mixture is neutralizedto a pH of 8 by the addition of hydrochloric acid. After cooling, theresulting precipitate is filtered off, washed with a minor amount ofice-cold water and dried. After recrystallization from water, the sodiumsalt of 4- benzyl-3-n-butylamino-5-sulfamylbenzoic acid is obtained as adihydrate with a melting point of 285290 C. (dec.) after loss of waterof crystallization at about 1 C..

4-benzyl-3 -n-butylamino-5- EXAMPLE 224-Benzyl-3-n-butylamino-5-sulfamylbenzoic acid Sodium4-benzyl-3-n-butylamino-S-sulfamylbenzoate dihydrate (ll.0 g.) isdissolved in hot water ml.) and the solution is acidified with aceticacid (10 ml.). The resulting precipitate is, after cooling, collected byfiltration and washed with water. After drying and recrystallizationfrom aqueous ethanol, 4-benzyl-3- n-butylamino-S-sulfamylbenzoic acid isobtained with a melting point of 234-235 C.. The material (IR, analysis)is identical with the material prepared as in Example 20.

EXAMPLE 23 4-Benzyl-3-n-pentylamino-5-sulfamylbenzoic acid By replacingin Example 21 the n-butanol by npentanol,4-benzyl-3-n-pentylamino-S-sulfamylbenzoic acid is obtained with amelting point of 23 l .5233 C..

EXAMPLE 24 4-Benzyl-3-(pyridyl-(2)-methylamino)-5- sulfamylbenzoic acidA mixture of 3-amino-4-benzyl-5-sulfamylbenzoic acid (1.02 g.),pyridine-Z-aldehyde (0.40 g.), p-toluenesulphonic acid (0.01 g.) andacetic acid (20 ml.)is hydrogenated in the presence of lt0 (mL) is g.).After about 2 hours the theoretical amount of hydrogen has been absorbedand the uptake becomes negligible. The mixture is then heated on a steambath and filtered hot to remove the catalyst. The filtrate is evaporatedin vacuo and the residue is crystallized by trituration with ethanol (10ml.). The material is collected by filtration and washed with ethanol.After drying and recrystallization from a mixture of ethanol andmethylcellosolve, 4-benzyl-3-(pyridyl-(2)-methylamino)-5-sulfamylbenzoic acid crystallizing with 0.25 mole of water is obtainedwith a melting point of 248249 C.

(dec.).

EXAMPLE 25 3-(Furyl-(2)-methylamino)-4-(4 '-methylbenzyl )'5-sulfamylbenzoic acid and its sodium salt A mixture of3-amino-4-(4-methylbenzyl)-5- sulfamylbenzoic acid (3.2 g., 0.0l mole),2 N sodium hydroxide (5.0 ml.) and ethanol ml.) is evaporated in vacuo.The precipitated sodium salt is dissolved in methanol (50 ml.), furfural(1.5 ml.) is added and the mixture is refluxed for 24 hours. Theresulting solution is left for 18 hours at room temperature, and is thencooled to 0-5 C. and stirred while sodium borohydride (0.8 g.) is addedin portions during about 1 hour. After additional stirringfor 3 hours,allowing the reaction mixture to reach room temperature, the solvent isremoved in vacuo. The residue is dissolved in water (30 ml.) and thesolution is acidified with acetic acid (5 ml.) to precipitate thereaction product as an oil. The oil is separated and dissolved in hotsaturated sodium hydrogene carbonate solution (30 ml.). The solution isfiltered hot in the presence of decolorizing carboil and, after cooling,the resulting precipitate is collected by filtration and washed with aminor amount of ice-cold water. After drying and recrystallization fromwater, the sodium salt of 3-(furyl-(2)-methylamino)-4- (4'-methylbenzyl)-5-sulfamylbenzoic acid is obtained. The purified salt isdissolved in hot water (l0 ml.) and the solution is acidified with 4 Nacetic acid (2 ml.).

After cooling, the precipitate is collected by filtration and washedwith water. After drying and recrystallization from ethanol,3-(furyl-(2)-methylamino)-4-(4'- methylbenzyl)-5-sulfamylbenzoic acid isobtained with a melting point of 234236 C. (dec.).

EXAMPLE 26 4-(4-Methylbenzyl)-3-(2-pyridyl-(4)-ethylamino)-5-sulfamylbenzoic acid A mixture of 3-amino-4-(4-methylbenzyl)-5-sulfamylbenzoic acid (1.2 g.), 4-vinylpyridine (1.0 ml.), acetic acid(0.4 ml.) and methanol (5.0 ml.) is refluxed for 3 hours. After cooling,the resulting precipitate is collected by filtration and washed withmethanol. After drying and recrystallization from methylcellosolve,4-(4-methylbenzyl)-3-(2-pyridyl-(4)- ethylamino)-5-sulfamylbenzoic acidis obtained with a melting point of 227228 C..

EXAMPLE 27 4-Benzyl-3-benzylamino-5-sulfamylbenzoic acid A mixture of4-benzylamino-6-carboxy-3-phenyl-l ,2- benzisothiazole-l ,l-dioxide(3.02 'g., 0.01 mole), 80 percent hydrazine hydrate (6.0 ml.), potassiumhydroxide (2.0 g.), water (4.0 ml.) and diethylene glycol (25 ml.) isstirred and refluxed for 3 hours. The temperature is then during about1.5 hours raised to 215 C. allowing volatile material to distil off, andfinally the reaction mixture is stirred at 2l5-220 C. for a further 3-4hours until the nitrogene evolution has ceased. After cooling, theresulting solution is diluted with water (25 ml.) and filtered in thepresence of decolorizing carbon. The filtrate is acidified with 4 Nhydrochloric acid (12 ml.) and the resulting precipitate is filtered offand washed with water. After drying and recrystallization from a mixtureof ethanol and methylcellosolve, 4-benzyl-3-benzylamino-5sulfamylbenzoicacid is obtained with a melting point of 24 8-249 C. (dec.). Thematerial (IR, analysis) is identical with the material prepared as inExample 7.

EXAMPLE 28 EXAMPLES 29 -36 By following the procedure described inExample 27 but replacing the 4-benzylamino-6-carboxy-3-phenyl-1,2-benzisothiazole-l ,l-dioxides by equimolar amounts of the5-N-substituted6-carboxy-3-phenyl-l,Z-benzisothiazole-l ,l-dioxides ofthe Table I following, the corresponding4-.benzyl-5-sulfamyl-N-substitutedanthranilic acids are obtained.

TABLE I Ex. S-substitutent of the N-substituent M.P. C.

No. 6-carboxy-3-phenyl (with l ,2-benzisothiadec.) zole-l 1 -dioxide 293'-methoxypro- 3-methoxy- 224-225 pylamino propyl 30 n-butylaminon-butyl 248-249 116 31 n-pentylamino n-pentyl 25l-252 32 iso-amylaminoiso-amyl 25l-252 33 benzylamino benzyl 256-258 34 4-chloroben- 4"chloro-259-26] zylamino benzyl 35 3-methylben- 3'-methyl- 232-234 zylaminobenzyl 36 B-phenylethyl- B-phenylethyl 245-246 amino The materialprepared as in Example 33 is identical (IR, analysis) withthe materialprepared as in Example 6.

EXAMPLE 37 Methyl 4-benzyl-3-n-butyl-S-sulfamylbenzoate To a solution of4-benzyl-3-n-butyl-5- sulfamylbenzoic acid (0.75 g.) in methanol (15ml.), concentrated sulphuric acid (0.25 ml.) is added and the mixture isrefluxed for 24 hours. After cooling, the resulting precipitate iscollected by filtration and washed with cold methanol. After drying andrecrystallization from methanol, methyl4-benzyl-3-n-butyl-5-sulfamylbenzoate is obtained with a melting pointof l53.5-155 C..

EXAMPLE 38 Cyanomethyl 4-benzyl-3-n-butyl-5 sulfamylbenzoate A mixtureof 4-benzyl-3-n-butyl-5-sulfamylbenzoic acid (0.72 g.),chloroacetonitrile (0.17 g.), triethylamine (0.22 g.) and dry acetone(7.0 ml.) is refluxed for 24 hours. After cooling, the separatedtriethylaminehydrochloride is removed by filtration and the filtrate isevaporated in vacuo. The residue is triturated with saturated sodiumhydrogenecarbonate solution (20 ml.) and the resulting crystallinematerial is collected by filtration and washed with water. After dryingand recrystallization from aqueous ethanol, cyanomethyl4-benzyl-3-n-butyl-5-sulfamylbenzoate is obtained with-a melting pointof l25l27 C..

We claim:

l. A compound of the general formula:

, 3 iNH-"R R CH 2 in which R, is a member of the class consisting ofunsubstituted hydrocarbon radicals with from three to eight carbon atomsin the chain and such radicals substituted by halogen, halo (lower)alkyl, including trifluoromethyl, and C and C alkox-y; phenylsubstituted methyl and ethyl groups, and R, is a member of theclass'consisting of unsubstituted, halogen and C -C alkyl substitutedphenyl radicals; and pharmaceutically acceptable salts; and esters ofthe compound of formula (I) with cyanomethanol, benzyl alcohol and C,-C,alcanols.

2. A compound according to claim 1, having the formula:

LcooH M... .H la

LoooH 6 (VII HgNO S in which R, is a member of the class consisting ofunsubstituted hydrocarbon radicals with from three to eight carbon atomsin the chain and such radicals substituted with halogen, halo (lower)alkyl, including trifluoromethyl, and C C, alkoxy; phenyl substitutedmethyl and ethyl groups, and R is a member of the class consisting ofunsubstituted, halogen and C, C,, alkyl substituted phenyl radicals; andpharmaceutically acceptable salts; and esters of the compound of formula(I) with cyanomethanol, benzyl alcohol and C C alcanols.

4. A compound of claim 1, in which R represents unsubstitutedhydrocarbon radicals with from three to eight carbon atoms in the chainand such radicals substituted with halogen, halo (lower) alkyl,including trifluoromethyl, and C C alkoxy; R, is a member of the classconsisting of unsubstituted, halogen and C -C alkyl substituted phenylradicals; and pharmaceutically acceptable salts; and esters of thecompound of formula (l) with cyanomethanol, benzyl alcohol and C -Calcanols.

5. A compound according to claim 1, in which R represents a benzylgroup; R is a member of the class consisting of unsubstituted, halogenand C -C alkyl substituted phenyl radicals; and pharmaceuticallyacceptable salts; and esters of the compound of formula (I) withcyanomethanol, benzyl alcohol and C,--C alcanols.

6. A compound according to claim 1, in which R, represents a phenetylgroup; R, is a member of the class consisting of unsubstituted, halogenand C -C alkyl substituted phenyl radicals, and pharmaceuticallyacceptable salts; and esters of the compound of formula (I) withcyanomethanol, benzyl alcohol and C -C alcanols.

7. 4-Benzyl-3-benzylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohols and C C, alcanols.

3-Benzylamino-4-(4'-methylbenzyl)-5- sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C,-C alcanols.

9. 3-Benzylamino-4-(2,4'-dimethylbenzyl)-5- sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C,-C alcanols.

10. 3-Benzylamino-4-(4'-chlorobenzyl)-5- sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C -C alcanols.

l1. 4-Benzyl-3-n-propylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C C alcanols.

12. 4-Benzyl-3-n-butylamino-S-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C,-C alcanols.

13. 4-Benzyl-3-n-pentylamino-S-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C -C alcanols.

14. 4-Benzyl-3-(2,3-dibromopropylamino)-S- sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C -C alcanols.

15. 4-Benzyl-3-allylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C -C alcanols.

16. 4-Benzyl-2-benzylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C -C alcanols.

' 17. 4-Benzyl-2-(3'-methoxypropylamino)-5- sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C -C alcanols.

18. 4-Benzyl-2-n-butylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C -C alcanols.

l9. 4-Benzyl-Z-n-pentylamino-S-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C -C alcanols.

20. 4-Benzyl-2-isoamylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C -C alcanols.

21. 4-Benzyl-2-benzylamino-S-sulfamylbenzoic acid .and pharmaceuticallyacceptable salts; and esters of thecompound with cyanomethanol, benzylalcohol and C -C, alcanols.

22. 4-Benzyl-2-(4'-chlorobenzylamino)-5- sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C -C alcanols.

23. 4-Benzyl-2-(3'-methylbenzylamino)-5- sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C,-C alcanols.

24. 4-Benzyl-2-(B-phenylethyl-amino)-5- sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol,

benzyl alcohol and C -C alcanols. t t I t

2. A compound according to claim 1, having the formula:
 3. A compound ofclaim 1, having the formula:
 4. A compound of claim 1, in which R1represents unsubstituted hydrocarbon radicals with from three to eightcarbon atoms in the chain and such radicals substituted with halogen,halo (lower) alkyl, including trifluoromethyl, and C1-C4 alkoxy; R2 is amember of the class consisting of unsubstituted, halogen and C1-C3 alkylsubstituted phenyl radicals; and pharmaceutically acceptable salts; andesters of the compound of formula (I) with cyanomethanol, benzyl alcoholand C1-C6 alcanols.
 5. A compound according to claim 1, in which R1represents a benzyl group; R2 is a member of the class consisting ofunsubstituted, halogen and C1-C3 alkyl substituted phenyl radicals; andpharmaceutically acceptable salts; and esters of the compound of formula(I) with cyanomethanol, benzyl alcohol and C1-C6 alcanols.
 6. A compoundaccording to claim 1, in which R1 represents a phenetyl group; R2 is amember of the class consisting of unsubstituted, halogen and C1-C3 alkylsubstituted phenyl radicals, and pharmaceutically acceptable salts; andesters of the compound of formula (I) with cyanomethanol, benzyl alcoholand C1-C6 alcanols.
 7. 4-Benzyl-3-benzylamino-5-sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohols and C1-C6 alcanols. 8.3-Benzylamino-4-(4''-methylbenzyl)-5-sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C1-C6 alcanols. 9.3-Benzylamino-4-(2,4''-dimethylbenzyl)-5-sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C1-C6 alcanols. 10.3-Benzylamino-4-(4''-chlorobenzyl)-5-sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C1-C6 alcanols. 11.4-Benzyl-3-n-propylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C1-C6 alcanols. 12.4-Benzyl-3-n-butylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C1-C6 alcanols. 13.4-Benzyl-3-n-pentylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C1-C6 alcanols. 14.4-Benzyl-3-(2,3''-dibromopropylamino)-5-sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C1-C6 alcanols. 15.4-Benzyl-3-allylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C1-C6 alcanols.
 16. 4-Benzyl-2-benzylamino-5-sulfamylbenzoicacid and pharmaceutically acceptable salts; and esters of the compoundwith cyanomethanol, benzyl alcohol and C1-C6 alcanols. 17.4-Benzyl-2-(3''-methoxypropylamino)-5-sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C1-C6 alcanols. 18.4-Benzyl-2-n-butylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C1-C6 alcanols. 19.4-Benzyl-2-n-pentylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C1-C6 alcanols. 20.4-Benzyl-2-isoamylamino-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C1-C6 alcanols.
 21. 4-Benzyl-2-benzylamino-5-sulfamylbenzoicacid and pharmaceutically acceptable salts; and esters of thecompoundwith cyanomethanol, benzyl alcohol and C1-C6 alcanols. 22.4-Benzyl-2-(4''-chlorobenzylamino)-5-sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C1-C6 alcanols. 23.4-Benzyl-2-(3''-methylbenzylamino)-5-sulfamylbenzoic acid andpharmaceutically acceptable salts; and esters of the compound withcyanomethanol, benzyl alcohol and C1-C6 alcanols.
 24. 4-Benzyl-2-( Beta-phenylethyl-amino)-5-sulfamylbenzoic acid and pharmaceuticallyacceptable salts; and esters of the compound with cyanomethanol, benzylalcohol and C1-C6 alcanols.